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Background: Neoadjuvant chemotherapy (NACT) is routinely used for patients with triple-negative breast cancer (TNBC). Upfront breast-conserving therapy (BCT) consisting of breast-conserving surgery (BCS) and adjuvant radiotherapy (RT) has been shown to be associated with improved outcome in patients with early TNBC as compared to mastectomy., Methods: We identified 2632 patients with early TNBC from the German Breast Group meta-database. Patients with cT1-2 cN0 and ypN0, available surgery and follow-up data were enrolled. Data of 1074 patients from 8 prospective NACT trials were available. Endpoints of interest were locoregional recurrence as first site of relapse (LRR), disease-free survival (DFS) and overall survival (OS). We performed univariate and multivariate Fine-Gray analysis and Cox regression models., Results: After a median follow-up of 64 months, there were 94 (8.8%) locoregional events as first site of relapse. Absence of pathologic complete response (pCR) was associated with increased LRR upon uni- and multivariate analysis (hazard ratio [HR] = 2.28; p < 0.001 and HR = 2.22; p = 0.001). Type of surgery was not associated with LRR. Patients in the BCS-group had better DFS and OS (DFS: HR = 0.47; p < 0.001 and OS: HR = 0.40; p < 0.001). BCS was associated with improved DFS and OS upon multivariate analysis (DFS: HR = 0.51; p < 0.001; and OS HR = 0.43; p < 0.001), whereas absence of pCR was associated with worse DFS and OS (DFS: HR = 2.43; p < 0.001; and OS: HR = 3.15; p < 0.001)., Conclusions: In this retrospective analysis of patients with early stage node-negative TNBC treated with NACT, BCS was not associated with an increased risk of LRR but with superior DFS and OS., Competing Interests: Declaration of competing interest DK reports honoraria from Merck Sharp & Dome, med update, onkowissen, best practice onkologie, ESO, ESMO, Astra Zeneca and Pfizer, advisory boards for Gilead as well as research funding from Merck KGaA, all outside the submitted work. MU declares honoraria from AstraZeneca, Art tempi, Amgen, Daiji Sankyo, Lilly, Roche, Pfizer, MSD Oncology, Pierre Fabre, Sanofi-Aventis, Myriad, Seagen, Gilead and Novartis; he also reports honoraria or fees for consulting or advisory role from Amgen, Lilly, Roche, Pfizer, Lilly, MSD, Pierre Fabre, Novartis, MSD Oncology, Roche, Agendia, Pierre Fabre, Seagen, Gilead, Lily, Stemline and Genzyme. All honoraria and fees paid to the employer/institution. TK reports honoraria from MSD, Pfizer, Gilead, Astra Zeneca, Daiichi Sankyo, Roche, Merit Medical, Endomagnetics, Sirius Medical, Hologic. AS declares grants from Celgene, Roche and AbbVie; personal fees from Celgene, Roche, Pfizer and AstraZeneca for travel expenses outside the submitted work. AS received honoraria from Roche, Celgene, Pfizer, AstraZeneca, Novartis, MSD, Tesaro, Lilly, Seagen, Gilead, GSK, Bayer, Amgen and Pierre Fabre outside the submitted work outside the submitted work. BA reports honoraria for lectures from Roche, Astra Zeneca, GSK, MSD, Celgene, Lilly, Novartis, Eisai and advisory board for MSD, GSK, Amgen, Sanofi-Aventis, Eisai. SS reports personal fees from Abbvie outside the submitted work. SS declares to be an employee of GBG Forschungs GmbH. GBG Forschungs GmbH received funding for research grants from Abbvie, Amgen, AstraZeneca, BMS, Daiichi-Sankyo, Gilead, Molecular Health, Novartis, Pfizer and Roche (paid to the institution); other (non-financial/medical writing) from Daiichi-Sankyo, Gilead, Novartis, Pfizer, Roche and Seagen (paid to the institution). GBG Forschungs GmbH has licensing fees from VMscope GmbH. In addition, GBG Forschungs GmbH has a patent EP21152186.9 pending, a patent EP19808852.8 pending, and a patent EP14153692.0 pending. VN declares to be GBG Forschungs GmbH employee. GBG Forschungs GmbH received funding for research grants from Abbvie, Amgen, AstraZeneca, BMS, Daiichi-Sankyo, Gilead, Molecular Health, Novartis, Pfizer and Roche (paid to the institution); other (non-financial/medical writing) from Daiichi-Sankyo, Gilead, Novartis, Pfizer, Roche and Seagen (paid to the institution). GBG Forschungs GmbH has licensing fees from VMscope GmbH. In addition, GBG Forschungs GmbH has a patent EP21152186.9 pending, a patent EP19808852.8 pending, and a patent EP14153692.0 pending. JH reports personal fees and non-financial support from Daiichi Sankyo, non-financial support from Hologic, personal fees from MSD Oncology, personal fees from Novartis, personal fees from Palleos Health Care, personal fees from Pfizer, personal fees from Roche Pharma, personal fees from Seagen, outside the submitted work. JH declares to be GBG Forschungs GmbH employee. GBG Forschungs GmbH received funding for research grants from Abbvie, Amgen, AstraZeneca, BMS, Daiichi-Sankyo, Gilead, Molecular Health, Novartis, Pfizer and Roche (paid to the institution); other (non-financial/medical writing) from Daiichi-Sankyo, Gilead, Novartis, Pfizer, Roche and Seagen (paid to the institution). GBG Forschungs GmbH has licensing fees from VMscope GmbH. In addition, GBG Forschungs GmbH has a patent EP21152186.9 pending, a patent EP19808852.8 pending, and a patent EP14153692.0 pending. SL reports institutional COIs: The institute receives grants and other from Abbvie, other from Amgen, grants and other from AstraZeneca, other from BMS, grants and other from Celgene, grants, non-financial support and other from Daiichi-Sankyo, other from Eirgenix, other from Eisai Europe Ltd, other from GSK, grants, non-financial support and other from Immunomedics/Gilead, other from Lilly, other from Merck, grants from Molecular Health, grants, non-financial support and other from Novartis, grants, non-financial support and other from Pfizer, other from Pierre Fabre, other from Relay Therapeutics, grants, non-financial support and other from Roche, other from Sanofi, non-financial support and other from Seagen, other from Olema Pharmaceutics, other from VMscope GmbH, outside the submitted work; In addition, Dr. Loibl has a patent EP21152186.9 pending, a patent EP19808852.8 pending, and a patent EP14153692.0 pending. All other authors report that they have no conflicts to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: To report the final results of the 5-year follow-up of the non-randomized SafeHER Phase III study (NCT01566721) describing the safety, tolerability, and efficacy of subcutaneous (SC) trastuzumab alone and in combination with concurrent or sequential chemotherapy., Methods: Patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) with no prior anti-HER2 therapy were included. SC trastuzumab was administered every 3 weeks for 18 cycles as adjuvant therapy with or without chemotherapy (concurrent or sequential). The primary objective was overall safety and tolerability of SC trastuzumab; efficacy was a secondary objective., Results: No new safety signals were observed during the final evaluation. The majority of adverse events (AEs) were grade 1 or 2 across the chemotherapy subgroups. Treatment discontinuation due to AEs was 5.1% for the intent-to-treat (ITT) population and similar for all chemotherapy subgroups. The overall disease-free survival (DFS) 5-year event-free rate in the ITT population (n = 2573) was 86.6% (95% CI, 85.2%-87.9%) with a median follow-up of 72 months. Based on chemotherapy timing, the no (n = 235), concurrent (n = 1533), and sequential (n = 805) chemotherapy subgroups had DFS 5-year event-free rates (95% CI) of 88.5% (83.4%-92.2%), 88.4% (86.6%-89.9%), and 82.6 (79.7%-85.2%), respectively., Conclusions: The 5-year follow-up analysis of the SafeHER trial demonstrating that SC trastuzumab has an acceptable safety profile, including cardiac toxicity, and efficacy for the treatment of HER2-positive EBC with and without chemotherapy, corresponding with historical data with trastuzumab., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Maintenance treatment with poly (ADP-ribose) polymerase (PARP) inhibitor is now the standard of care in patients with BRCA-mutated platinum-sensitive recurrent ovarian cancer following response to chemotherapy. In the SOLO2 trial, adverse event (AE)-associated olaparib interruption, dose reduction, and discontinuation occurred in 50%, 28%, and 17% of patients, respectively. We used data from the SOLO2 trial to evaluate the impact of dose alterations on survival outcomes and identified baseline characteristics associated with dose alteration., Patients and Methods: We computed relative dose intensity (RDI) defined as the received dose as a percentage of the standard dose (300 mg twice a day) during the first 12 weeks on treatment. Patients were categorized into RDI >98%, RDI 90%-98%, and RDI <90%. The association between RDI categories with progression-free survival (PFS) and overall survival (OS) were examined using a 12-week landmark Cox regression analysis. Logistic regression analysis was used to correlate baseline factors with RDI at 12 weeks., Results: In patients on olaparib included in the landmark analysis (n = 185), the mean 12-week RDI was 91.4%. There was no significant difference across 12-week RDI >98% (n = 110), 90%-98% (n = 29), and <90% (n = 45) categories for PFS (median, 14.2 versus 19.3 versus 34.4 months; P = 0.37) and OS (median, 49.7 versus 49.5 versus 54.1 months; P = 0.84). Risk of RDI ≤90% increased with baseline performance status 1 [odds ratio (OR): 2.54; 95% confidence interval (CI): 1.11-5.82] any nausea (OR: 3.17; 95% CI: 0.9-11.23), and with body weight ≤70 kg (OR: 1.86; 95% CI: 0.92-3.76)., Conclusions: Dose reduction and interruption for the management of olaparib-associated AEs during the first 12 weeks did not impact on PFS and OS. When counselling patients requiring dose reductions or interruptions due to AEs, the results of this study will help assure patients that their outcomes will not be adversely affected., Competing Interests: Disclosure KEF reports intuitional funding from AstraZeneca (AZ). MF reports institutional funding from AZ, Novartis, and Beigene; consulting fees from AZ, Novartis, GlaxoSimthKline (GSK), Merck Sharp & Dohme (MSD), Takeda, and Lilly; honoraria for lectures from AZ, GSK, and ACT-Genomics; travel support from AZ; and participation in a data advisory role with Australasian Gastro-Intestinal Cancer Trials Group and Independent Data and Safety Monitoring Board. IRC reports personal fees and travel support from AZ, GSK, and Clovis Oncology; and personal fees from Roche, Mersana, Deciphera, Eisai, Amgen, Bristol Myers Squibb, OncXerna, and Aravive. AC reports institutional research funding from AZ; payment from Clovis Oncology for lectures and travel support; and he participates in an advisory role to AZ. RP reports institutional funding from AZ. He participates in an advisory role to AbbVie, AZ, Care4ward (unpaid), Clovis Oncology, Curio Science, Eisai Inc., Genentech, Janssen Oncology (J&J), Merck & Co., Mersana Therapeutics, Inc., NewLink Genetics, Nexus Global Group, Pieris Pharma Inc., Roche, Inc., Sutro Biopharma, Syndax Pharmaceuticals, Tesaro Inc., Vascular Biogenics Ltd. NC reports grants, consulting fees, and personal fees from AZ; consulting fees and personal fees from GSK; and personal fees from Tesaro, Novartis, Clovis, MSD, GSK, EISAI. She participates in an advisory role with Roche, PharmaMar, AZ, Clovis Oncology, MSD, GSK, Tesaro, Pfizer, BIOCAD, ImmunoGen, Mersana, OncXerna, and Eisai. KF reports institutional research funding and honoraria for lectures from AZ. GS reports institutional research funding from AZ, MSD, Novartis, and Roche; and consulting fees paid to the institution from BioViva and Segen. IV reports receiving institutional fees from Oncoinvent AS and Genmab; grant funding from Amgen and Roche; consulting fees from Aksebio, Amgen, GmbH, AZ, Clovis Oncology, Carrick Therapeutics, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, Roche, Genmab, GSK, Immunogen Inc., Jazz Pharma, Karyopharm, Mersana, Millennium Pharmaceuticals, MSD, Novocure, Novartis, Octimet Oncology NV, Oncoinvent AS, Sotio a.s., Verastem Oncology, Zentalis; and travel expenses from Amgen, MSD, Tesaro, AZ, Roche. EPL reports medical writing assistance for the primary SOLO2 publication from AZ; institutional grants from AZ and Merck; personal payments for lectures from AZ and GSK; and participation in an advisory role with Incyte, Roche, and Pfizer. He reports other interests including as an employee of ARCAGY GINECO research group. CKL reports institutional payments from Roche, AZ, and Merck KGA; and personal payments for lectures, presentations or travel support from AZ, Amgen, Takeda, Boehringer Ingelheim, Pfizer, Yuhan, Merck KGA, Roche, and MSD. All other authors have declared no conflicts of interest., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Introduction: We aimed to evaluate real-life experiences with the re-challenge of poly(ADP-Ribose)Polymerase (PARP) inhibitors (PARPi) after a prior PARPi therapy in patients with recurrent EOC., Methods: A retrospective descriptive study was conducted at a tertiary care center of excellence for ovarian cancer. Demographic, pathological, and therapeutic data were collected for patients with recurrent epithelial ovarian cancer who were re-treated with PARPi in their therapy course., Results: Twenty-nine patients were included in the study. Twenty-six patients received the second PARPi as maintenance therapy after two different lines of therapy and three patients received the second PARPi as upfront therapy after progression. Most of the patients (57.7%) were exposed to first PARPi after a second-line therapy. The median progression-free survival under the first and second PARPi therapy was estimated at 15 and 7 months respectively. PFS under the second PARPi after platinum-based chemotherapy was better after a complete remission with a median PFS of 8.5 months, compared to patients with partial remission (5.5 months). A better PFS was noted in case of negative BRCA status under the second PARPi therapy (median PFS of 7.4 vs. 4.5 months, p = 0.11). The second PARPi therapy was mainly discontinued due to disease progression (84.6% of the cases). Discontinuation of treatment with the second PARP due to toxicity was needed in one case who developed a myelodysplastic syndrome., Conclusion: Real-life data support prospective evidence that patients with recurrent EOC may derive benefit of the re-treatment with PARPi in case of clear response to the last platinum-based therapy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier Inc.)

Background: With the growing importance of neoadjuvant systemic therapy (NST) the assessment of post neoadjuvant axillary status is of increasing importance especially in patients who presented initially with suspicious nodes (cN1). This study aims to investigate the predictive value of palpation and axillary ultrasound of formerly cN1 patients following NST., Patients and Methods: The SENTINA trial (SENTinel NeoAdjuvant) is a 4-arm prospective multicenter study designed to evaluate the role of sentinel node biopsy (SLNB) in the context of neoadjuvant systemic treatment (NST) of breast cancer patients., Results: 1240 patients from 103 institutions entered the trial. 715 (arm C n = 592; arm D n = 123) patients, who presented initially cN1 underwent clinical evaluation of lymph node status following NST. Palpation alone demonstrated a sensitivity of 8.3%, specifity of 94.8% and a negative predictive value (NPV) of 46.6%. Ultrasound alone revealed a sensitivity of 23.9%, specificity 91.7%, and a NPV of 50.3%.The investigators combined classification (palpation and ultrasound) resulted in a sensitivity of 24.4%, specificity 91.4%, and a NPV of 50.3%. Investigators classified the axilla nodes as being unsuspicious (cN0) following NST in 592/715 patients; of them 298 (50.3%) were pN0, 151 (25.5%) had 1-2 histologically involved nodes and 143 (24.2%) had >2 histologically involved nodes., Conclusion: The diagnostic accuracy of ultrasound and palpation following NST is unacceptably low and additional tools for evaluation of the axillary lymph node status following NST are urgently needed., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Secreted protein acidic and rich in cysteine (SPARC) has been suggested as a new biomarker and therapeutic target in breast cancer, as well as other tumor types., Patients and Methods: We evaluated the frequency of SPARC expression among different molecular breast cancer subtypes and its role for therapy response after neoadjuvant chemotherapy. In this study, pretherapeutic core biopsies of 667 patients from the neoadjuvant GeparTrio trial were evaluated for SPARC expression by immunohistochemistry using a standardized immunoreactive score (IRS)., Results: An increased SPARC expression (IRS ≥6) was observed in 26% of all tumors. In triple-negative tumors, SPARC expression was increased in 37% of tumors, compared with other molecular subtypes (23% HR+/HER2-, 29% HR+/HER2+ and 22% HR-/HER2+; P = 0.038). Increased SPARC expression was associated with an increased pathological complete response (pCR) rate of 27%, compared with 15% in tumors with low SPARC expression (P < 0.001). In the triple-negative subgroup, pCR rates were 47% in tumors with high SPARC expression, compared with 26% in tumors with low SPARC expression (P = 0.032). In multivariable analysis, SPARC was independently predictive in the overall population (P = 0.010) as well as the triple-negative subgroup (P = 0.036)., Conclusions: SPARC is frequently expressed in breast cancer with triple-negative breast cancer revealing the highest expression rate. High SPARC expression of the primary tumor is associated with a higher chance of achieving a pathological complete remission after TAC or TAC-NX chemotherapy. As SPARC is an albumin-binding protein and might mediate intratumoral accumulation of albumin bound drugs, SPARC should be further evaluated as a predictive marker especially for response to albumin-bound drugs like nab-paclitaxel., Clinical Trial Number: NCT00544765., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Hormone and human epidermal growth factor receptor 2 (HER2) receptors are the most important breast cancer biomarkers, and additional objective and quantitative test methods such as messenger RNA (mRNA)-based quantitative analysis are urgently needed. In this study, we investigated the clinical validity of RT-PCR-based evaluation of estrogen receptor (ESR1) and HER2 mRNA expression., Patients and Methods: A total of 1050 core biopsies from two retrospective (GeparTrio, GeparQuattro) and one prospective (PREDICT) neoadjuvant studies were evaluated by quantitative RT-PCR for ESR1 and HER2., Results: ESR1 mRNA was significantly predictive for reduced response to neoadjuvant chemotherapy in univariate and multivariate analysis in all three cohorts. The complete pathologically documented response (pathological complete response, pCR) rate for ESR1+/HER2- tumors was 7.3%, 8.0% and 8.6%; for ESR1-/HER2- tumors it was 34.4%, 33.7% and 37.3% in GeparTrio, GeparQuattro and PREDICT, respectively (P < 0.001 in each cohort). In the Kaplan-Meier analysis in GeparTrio patients with ESR1+/HER2- tumors had the best prognosis, compared with ESR1-/HER2- and ESR1-/HER2+ tumors [disease-free survival (DFS): P < 0.0005, overall survival (OS): P < 0.0005]., Conclusions: Our results suggest that mRNA levels of ESR1 and HER2 predict response to neoadjuvant chemotherapy and are significantly associated with long-term outcome. As an additional option to standard immunohistochemistry and gene-array-based analysis, quantitative RT-PCR analysis might be useful for determination of the receptor status in breast cancer.

Expression of the Bcl-2 protein confers resistance to chemotherapy-mediated apoptotic signals in patients with breast cancer. We investigated effects of Bcl-2 down-regulation by the Bcl-2 antisense oligodeoxynucleotide oblimersen in breast tumor biopsies. Oblimersen targets Bcl-2 messenger RNA (mRNA), down-regulates Bcl-2 protein translation and enhances antitumor effects of subtherapeutic chemotherapy doses. Within a phase I trial, we administered escalating doses of oblimersen (3, 5 or 7 mg/kg/day) as continuous infusion on days 1-7 in combination with standard-dose docetaxel (Taxotere), Adriamycin and cyclophosphamide (TAC) on day 5 as preoperative chemotherapy in 28 patients with T2-4 tumors. Effects of oblimersen were evaluated in tumor biopsies and peripheral blood mononuclear cells (PBMCs) 4 days after start of oblimersen and before TAC treatment by quantitative microfluidic real-time PCR. Read-outs consisted in measurement of Bcl-2 mRNA modulations and of 18 putative predictive markers. Two of 13 patients showed a diminution of Bcl-2 transcripts after 4 days of treatment with oblimersen 5 mg/kg/day. PBMCs could not be evaluated as a surrogate tissue because no qualified RNA could be isolated. Nevertheless, we demonstrated feasibility to process clinical samples and to obtain good quality RNA from tumor biopsies and indicated the potential of oblimersen to lower Bcl-2 mRNA in breast cancer.